Thyroid hormones, such as thyroxine (T4). L-thyroxine (LT4) and 3,5,3′-triiodo-L-thyronine (T3), and their analogs such as GC-1, DITPA, tetrac and triac, regulate many different physiological processes in different tissues in vertebrates. It was previously known that many of the actions of thyroid hormones are mediated by the thyroid hormone receptor (“TR”). A novel cell surface, integrin αvβ3 receptor for endogenous thyroid hormone (L-thyroxine, T4, T3) has been identified. The αvβ3 receptor however, is not a homologue of the nuclear thyroid hormone receptor (TR), but rather, a cell surface receptor that is capable of performing a number of nucleus-mediated events, including pro-angiogenic action of thyroid hormone.
Tetraiodothyroacetic acid (tetrac) is a deaminated analog of T4 that has no agonist activity at the integrin. Instead, tetrac inhibits binding of T4 and T3 to the integrin and the pro-angiogenic action of thyroid hormone analogs at αvβ3. Inhibition of the angiogenic action of thyroid hormone has been shown in the chick chorioallantoic membrane (CAM) model, in the vessel sprouting model involving human dermal microvascular endothelial cells (HDMEC), and in vivo in the mouse matrigel angiogenesis model.
In the absence of thyroid hormone, tetrac blocks the angiogenic activity of basic fibroblast growth factor (bFGF, FGF2), vascular endothelial growth factor (VEGF) and other pro-angiogenic factors.
Circulating levels of thyroid hormone are relatively stable. Thyroid hormone may increase activity of small molecules that support neovascularization (bradykinin, angiotensin II) and stimulate endothelial cell motility. Therapeutic angio-inhibition in the setting of cancer may be opposed by endogenous thyroid hormone, particularly when a single vascular growth factor is the treatment target. This may be a particular issue in management of aggressive or recurrent tumors. Membrane-initiated actions of thyroid hormone on neovascularization, cell proliferation, membrane ion channels or gene expression effects of the hormone, mediated by thyroid receptors, may be assumed to contribute to “basal activity” or set-points of life processes in intact organisms. The possible clinical utility of cellular events that are mediated by the membrane receptor for thyroid hormone may reside in inhibition of such effect(s) in the contexts of neovascularization or tumor cell growth. Indeed, it has been shown that blocking the membrane receptor for iodothyronines with tetraiodothyroacetic acid (tetrac), a hormone-binding inhibitory analog that has no agonist activity at the receptor, can arrest growth of glioma cells and of human breast cancer cells in vitro.
Despite the promising results of anti-angiogenic pharmaceuticals, angioinhibition as a treatment option for various cancers and debilitating diseases has been met with varying degrees of success. Elevated levels of endogenous circulating pro-angiogenic thyroid hormone in patients receiving anti-angiogenic therapy can lead to resistance in the host patient. This development in resistance may lead to previously successful treatments becoming ultimately ineffective. Therefore, there is a need for an assay to identify and screen for patients who have developed or are at risk of developing a resistance to the anti-angiogenic treatments. Moreover, there is also a need for a treatment and prophylactic method to prevent the formation of the anti-angiogenic resistance in patients.